Pain is the most frequently reported symptom and is a common clinical problem confronting the clinician. Millions of people in the United States suffer from severe pain that, according to numerous recent reports, is chronically under-treated or inappropriately managed.
Opioids have long been recognized as one of the most effective treatments of pain. However, they also have a high potential of abuse. In fact, opioid and narcotic abuse are major worldwide problems connected with tremendous social and personal strife. As of 1992, the estimated United States economic cost of drug and alcohol abuse was $246 billion. A recent National Household Survey on Drug Abuse survey conducted by the Substance Abuse and Mental Health Services Administration reported in July 2007 that nearly one in twelve full-time workers in the United States have serious enough drug/alcohol problems to require medical treatment. Providing recovery assistance for drug addicts and alcoholics with pharmacological interventions has proven helpful.
Certain opioids, such as buprenorphine (BUP), butorphanol, dezocine, meptazinol, nalbuphine and pentazocine, have both agonist and antagonist qualities. For example, the main agonist-antagonist effect of buprenorphine is through its binding to μ-opioid and κ-opioid receptors, acting clinically as an agonist at lower doses and as an antagonist at higher doses. The dual agonist-antagonist activity of these opioids make them effective at not only treating pain, but also at reducing the severity of the withdrawal symptoms experienced when a former abuser begins to eliminate opioid and/or alcohol. Buprenorphine is currently available as a sublingual dosage form, both alone (Subutex®) and in combination with naloxone (Suboxone®) for the treatment of pain and opioid dependence. The sublingual administration of these formulations results in clinically relevant drawbacks. For example, the necessity of taking multiple daily doses, or even once-daily dosing, decreases patient compliance. In addition, the daily and multiple daily dosing necessary with sublingual dosage forms may cause more frequent and more extreme peaks and troughs in the blood-plasma concentration of the active medications. These peaks and troughs increase the potential for a patient to experience both the adverse effects associated with supra-therapeutic concentrations and ineffective relief associated with below therapeutic concentrations. Additionally, many sublingual tablets have a bitter taste, which reduces patient compliance.
Further, patients undergoing withdrawal from narcotic or alcohol abuse and those suffering from chronic, under-treated or intractable pain often also suffer from a lack of appetite, nausea and/or frequent emesis. As such, oral and sublingual therapies for these patients are often either poorly tolerated or fail to provide an effective therapeutic dose.
For these patients, transdermal administration can provide a favorable route of administration. Transdermal dosing provides the patient with a desirable systemic delivery profile which can minimize or eliminate any “highs” (dizziness and drowsiness) associated with more rapid absorption and can reduce the side effects associated with oral administration of a drug, such as abdominal pain, nausea and vomiting. Additionally, transdermal administration avoids first-pass metabolism which can allow for higher therapeutic concentrations to be achieved, and also offers a patient freedom from injections and surgical implantations. Transdermal delivery can also improve patient compliance by reducing the dose frequency. A transdermal patch can offer sustained release of a drug for an extended period (e.g., one week).
Because of the inherent potential for abuse, it is important that any pharmaceutical composition containing an opioid agonist or opioid agonist-antagonist or prodrugs of either be made as abuse-resistant or abuse-deterrent as possible. This is particularly true with extended release opioid products, including transdermal applications. Illicit users often will attempt to circumvent the extended release properties of these dosage forms by injecting, chewing or otherwise misusing or abusing the product in order to achieve an immediate release of the opioid agonist, opioid agonist-antagonist or prodrugs of the foregoing.
The Food and Drug Administration (“FDA”) has recently emphasized the importance of reducing the risk of opioid abuse. In a Feb. 9, 2009 press release, the FDA publicly announced a program in which it would meet with the manufacturers of extended release and transdermal opioids regarding opioid misuse and abuse. Under the terms of the announced program, the manufactures will be required to develop Risk Evaluation and Mitigations Strategies to ensure proper opioid use.
Thus, it would be desirable to transdermally administer an opioid agonist or agonist-antagonist, such as buprenorphine, where the formulation or dosage form used to deliver the opioid agonist or agonist-antagonist is resistant to possible abuse or other illicit diversion.